The severe diabetic nephropathy case of christopher goodwood

The severe diabetic nephropathy case of christopher goodwood

The Severe Diabetic Nephropathy Case of Christopher Goodwood

As according to the case of Christopher Goodwood, from his birth as a child he was normal in overall intellectual and physical aspects till the age of 12 years and at 12 years of age he showed the symptoms of diabetes mellitus which helped to diagnose it easily. Diabetes or Diabetes mellitus is a metabolic disease in which the blood sugar levels are elevated due to defect in the production or secretion of insulin and to make up its need in the body. If the body does not produces proper quantity of insulin to breakdown glucose from blood for moving into the cell, than excessive glucose will accumulate in the blood and will pass away through urine in prolong condition of diabetes, causing symptoms and complication of diabetes mellitus like Diabetic Hyperglycaemia, Proteinuria, diabetic nephropathy and cardiovascular diseases.

Diabetes mellitus is of two type; 1) Type 1 i.e. Insulin Dependent Diabetes mellitus (IDDM) and Type 2 i.e. Non-Insulin Dependent diabetes Mellitus (NIDDM). Type 1 or IDDM is a multifactorial disorder which is considered to be a severe cause of insulin deficiency caused by chronic and advanced damage of pancreatic beta-cells due to immune response. The autoimmunity against pancreatic beta-cells is probably triggered by environmental factors working in the circumstance with predisposing genetic background (Pirot P etal,2008).

IDDM is an autoimmune disease were pancreatic islet cells are infiltrated and damaged by autoreactive CD4+ and CD8+ T lymphocytes. That shows that Th1 cells are the initial mediators of β-cell damage causing disease. The inflammatory response stimulated by Th1 cells that are characterised by the formation of interferon (IFN) - γ and interleukins (IL) -2. Th2 cell then regulate humoral immune response and release IL -4 and IL -10. Development of Th1 cells, IL -4 are stimulated by IFN-γ and IL -12 is required for differentiation of Th2 cells. Cytokines IFN -γ and IL -4 and IL -10 decline the control of Th2 and Th1 effector cell differentiation and function, respectively. Hence, the Th cells and cytokines reaction caused by environmental agent can be a factor responsible to initation and or progression of IDDM. (Kraine M.R, etal, oct 1999).

The keto-acidosis and the biochemical marks of IDDM are so profound in insulin shortage that it will continue to grow unless insulin substitution in administered (Barnett A.H, 2006). The early symptoms of ketoacidosis are frequent thirst and urination, weight loss, nausea and fatigue and abdominal pain in children (Kishore P, June 2008). Also due to hampering production of insulin, the breakdown of glucose is reduced and for prolong duration affects the kidneys hyperfiltration process, causing the loss of proteins into urine, flowing through the blood vessels passing through glomeruli. Loss of protein into the urine can be due to damage walls of blood vessels, which is detected at very low concentration in urine. Due to continue leakage an individual is more prone to develop high blood pressure and loss of protein through urine (proteinuria). It prominently occurs in individual causing uremia and generates requirement of dialysis, but 1/3 of the people with diabetes will develop microalbuminuria and its associated risk of permanent kidney damage. (Hanas R, 1998;).

As mentioned above, it was seen that in the case of Christopher that he suffered excessive thirst so he consumed 3 litres of liquid per day that had caused frequent urination and also loss of protein in urine which caused elevation in the blood pressure. His serum creatinine test finding showed that it was higher as 7.5mg/dl compared to normal which is lower than 1.0mg/dl. This suspected that he was suffering from diabetic complication of kidney or Diabetic Nephropathy. The reason for the cause of diabetic nephropathy is due to increasing blood pressure, determined proteinuria and decreased glomerular filtration rate (GFR). The total protein elimination of 0.5/day is equivalent to excretion of a urinary albumin of about 300mg/day or 200ug/min (Pickup J.C, etal, 1994;). The diabetic nephropathy is caused by subclinical rise in albumin elimination up to maximum normal range but lower than the limit specifying diabetic nephropathy. This amount of albumin in urine is known as Microalbuminuria. Diabetic nephropathy happens in both IDDM and NIDDM, but the prevalence is more in IDDM ranging about 15-20%, whereas remaining 15-28% of the patients exhibit determined microalbuminuria (Pickup J.C, etal, 1994;). It occurs majorly in males compared to females, also to patients possessing diabetes before the age of 15 and then after that age.

Chronic complication of diabetes by pickup J. figure 13.3 pg no: 141

The occurrence of Proteinuria and loss of blood cells from urine are one of the causes of glomerulosclerosis. Glomerulosclerosis is not identical with diabetic nephropathy as diabetic glomerulosclerosis is seen in almost all IDDM patients suffering from 10 years of diabetes, while diabetic nephropathy will occur in only 35-40% of diabetic patient. As the gomerulosclerosis was identified in the case of Christopher through kidney biopsy, as small cut section of kidney tissue, which revealed the imminent danger of kidney failure, thus he was suggested for haemodialysis twice a week. Gomerulosclerosis is caused by stimulation of glomerular cells to generate scar material or hardening of the small blood vessels of glomeruli inside kidney, during different sclerotic situation causing diseases like diabetes or lupus etc. The scarring of kidney increases the glucose levels leading to increase in the force for blood flow in kidney, causing stress over the filtration through glomeruli, which elevates the blood pressure (Glomerular Disease, 22 march 2010). Also the Glomerular Filtration Rate (GFR) increases on the onset of IDDM but falls down when Albumin Excretion Rate (AER) is between 100 and 300mg/day, with an average rate of about 10ml/min/1.73m2 per day (Pickup J.C, etal,1994;). The fall in GFR is due to decrease in the glomerular surface area, which is compressed by albuminuria due to mesangial expansion that appears so obvious that GFR cannot be regulated by this mechanism. This causes permanent decline in GFR and once GFR is below 50ml/min/1.73m2, causes serum creatinine to increase leading to unavoidable decline toward End-Stage Renal failure ESRF, which is quite persistent for the current patient but may vary with patients (Pickup J.C, etal,1994;).

Moderate decrease in GFR with or without other evidence of kidney damage.

30-59

4

Severe decrease in GFR with or without evidence of kidney damage

15-29

5

Established renal failure.

<15(or on dialysis)

Genetic Background of IDDM.

The risk of developing IDDM increases in some loci, which include the human leukocyte antigen HLA locus, is the most common influencing polymorphism, which gene that codes for major histocompatibility complex (MHC) molecules. They are of two types: 1) MHC class I: - present in every nucleated cell in the body and responsible for presenting intracellular antigens, whereas MHC class II: - are situated on the antigen presenting cells (APC) and help to recognise extracellular antigen. MHC class II are available in three different forms: DR, DQ and DP, which are made of two chains (α and β) that are determined by genes A and B. The MHC class II genes are the main risk factor for development of IDDM are located on chromosome 6p21.3-HLADQB1, DQA1, HLA DRB1 includes HLA DRB3 and DRB4 refer as IDDM genes which causes as much as 50% of risk along with other non-MHC genes including insulin and individual with both DR3 and DR4 are mostly subjected to IDDM, equally DR2 allele is defensive (Platz P, etal,). As in the case of Christopher is HLA type include HLAA2, 24; B50, 51; DR3, 4; having inherited the allele DR3, which responsible for the cause of his IDDM that eventually led to kidney damage.

Environmental factors responsible for IDDM.

The environmental factors most considered are viruses, diet, toxin and stress, in order of suspected involvement in the cause of IDDM. Viruses can affect β cells by two mechanisms i.e. direct toxicity of β cells and other by triggering an autoimmune response that stimulates β cells. The following viruses that cause the induction and development of IDDM are Mumps, Rubella virus and enteroviruses are the most possible candidates for activating beta-cell autoimmunity. The entrovirus has an exact tropism for pancreas that enables it to harm human islets from non-diabetic patient indirectly causing reduced glucose stimulated insulin release. Dietary study of the effect of cow's milk, human breast milk, N-nitroso compounds, bovine serum albumin, gluten, fat and proteins on the development of IDDM are numerous, but their direct relation for the cause of disease are not proven( Kraine M. R, etal,oct 1999;).

Hence, the end stage renal disease caused kidney failure, where the kidney graft was obtained and transplant was performed. Kidney functioned normally for some days and then rejection occurred. Donor organs were obtained from cadaver or living donor. The immune response generated for transplanted tissue or organ is regulated by genetic variation between donor and recipient is related to different antigenic variations of highly polymorphic HLA molecules. While transplanting the organ, alloreaction is generated by the recipient immune system are directed at the cells of the graft and destroy them, this process is called transplant rejection. There are four type of graft transplant rejection 1)Autograft, 2) Isograft, 3) Allograft, 4) Xenograft. 1) Autograft is the transfer of self-tissue form one individual site to other same individual. 2) Isograft is transfer of tissue between genetically identical individuals. 3) Allograft is transfer of tissue between genetically different individual of the same spices. As Christopher's kidney graft was from genetically different individual of the same species, he underwent allograft rejection. Rejection is categorized as acute and chronic, can occur at any time. Acute rejection occurs normally in the initial months after transplantation and contains a cellular response with the proliferation of T lymphocytes. Chronic rejection happen after months or years of transplantation as it is caused by both cellular and humoral immunity, it does not respond to immunosuppressive therapy (Porth C.M, etal,2009;).

The causes of acute rejection are effector T cells stimuli to HLA variation between donor and recipient. The transplant recipient T cells pool includes clones of alloreactive T cells that are exact for HLA allotypes of the transplanted tissue which are not shared with the recipient. The effector CD 4 and CD 8 T cells are responded by alloreactive T cell, which can attack the organ graft and destroy it. This is called acute rejection. To avoid acute rejection all the transplanted patients are administered with immunosuppressive drugs before and after transplantation. The inflamed transplanted organ stimulates the organ's dendritic cells. Different sets of peptide are bound by different HLA allotypes; each selects different T cells receptor during thymic selection. Thus, the T cells range selected by the recipient HLA type having numerous clones that reacts to HLA self- peptide complex presented by donor cells of various HLA types. The clones of alloreactive T cells possess memory phenotype, that reveals their origin of stimulation and expand to the stimuli to pathogens and cross over with reactive HLA. This type of alloreactive response is stimulated directly by receptor with the allogeneic HLA molecules expressed by donor dendritic cells is called direct pathway of allorecognition (Parham P, 2005;). Where T cells migrates through transplanted tissue, where Th1 cells activates the resident macrophage inflame the tissue further and Cd8 T cells systematically destroy the transplanted tissue (Parham P, 2005;).

The other way by which HLA alloantigens on transplant that can be suggested to the recipient's immune system to produce response. The HLA molecules from membrane fragments through apoptotic cells are taken up by dendritic cell of the transplant recipient and administered such that peptide derived from the donor HLA allotype are offered by the recipient's HLA allotypes. Due to endocytic way of uptake along with most of the peptide from HLA type I or II, will be offered by the HLA type II allotype of the recipient. This complex will facilitate a CD4 T cells alloreaction, when different peptide in amino acid sequence from those produced by degradation of the recipient own HLA allotype. This alloreactive CD 4 T cells are specific for the complex of the peptide obtained from the HLA allotype donor HLA allotype attached to a recipient HLA class II allotype. This process of stimulating alloreactive T cells is called indirect pathway of allorecognition, because alloreactive T cells do not directly identify the transplanted cells but recognize subcellular material present that has been processed and presented by allologous cells. T cells that causes indirect pathway of allorecongnition supported for acute rejection of transplanted organ are less in number compare to stimulate by direct pathway. (Parham P, 2005;)

Hence, appropriate alternative for kidney rejection has to be found, whereas, the only current alternative for kidney failure was kidney transplantation, there is no other current alternative other than dialysis and kidney transplant. But there are further research going on kidney related to stem cell. With the increasing rate of end-stage renal failure and limited alternatives for its treatment, stem cell (SC) therapy for kidney injury is urgently needed. Choosing the right SC type is the critical step in realizing the potential of this therapeutic approach. Four possible sources of SCs are envisioned for the development of this type of treatment: (i) bone-marrow-derived SCs (BMSCs), (ii) renal adult SCs, iii) embryonic SCs and (iv) fetal renal SCs. (Sagrinati C, etal, 2008;)

Figure 5: - Schematic representation of distinct therapeutic approaches for cell therapy of renal injury and of the multiple mechanisms that account for the regenerative potential of different types of stem cells (SCs) in renal tissue injury. ( Sagrinati C, etal,2008,Stem-cell approaches for kidney repair: choosing the right cells, figure 1)

Bone marrow derived stem cells (BMSCs)obtained from autologous sources and differentiated in the form of glomerular and tubular cells, even though their outputs are unaccepted. Also they possess immunomodulation potential and release growth factor that causes tubular cell proliferation and vascular cell protection, leading to renal tissue regeneration. The renal stem cells (SC) produced by adults, might be ideal for tissue replacement, as they cannot differential into self-renal cells and non-self-renal cells. SC are derived from autologous kidney and given their high self-renewal potential can be increased to obtain more cells for treatment, thus restricting the need for immunosuppressive therapy. ESC's have highest differentiation capacity but face ethical barriers and also have the greatest risk for teratoma formation.

Fetal kidney-specific SCs shows more regenerative characteristic and, at variance with ESCs, do not show tumorigenic potential, but they also have to be obtained from allogeneic sources (Sagrinati C, etal, 2008;).

Hence, it concluded that Christopher Goodwood suffered from early diabetes mellitus, which after prolong duration caused diabetic nephropathy leading to end stage kidney failure. Then he was grafted with cadaveric kidney of 20 years old man, who was younger than his age. He was also administered with anti- ICAM antibody during transplant and was stopped immediately, which might be one of the causes of rejection. Age of the donor is one of the other factors of rejection.

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